After initial mechanical insult, Traumatic Brain Injury (TBI) is characterized by a dynamic process of secondary injury that involves chronic neuroinflammation which is implicated in long-term cognitive and motor impairments and impacts recovery of function. Complement activation is a major component of the inflammatory cascade, and there is increasing evidence that complement plays a role in propagating injury after TBI, at least in the acute phase. However, complement can also contribute to homeostatic and reparative mechanisms after brain injury, and we have demonstrated in a stroke model that the alternative pathway is an optimal target for therapy because its inhibition reduces pathologic amplification of complement activation, but does not interfere with other complement pathways thought to be important for maintenance of homeostatic activity and reparative mechanisms in the CNS. Based on our work in stroke models and preliminary data in a TBI model, in this pilot study we will investigate the characteristics of the chronic inflammatory response after murine TBI (controlled cortical impact, CCI) and investigate the effects of chronically administered alternative complement pathway inhibitors that are specifically targeted to the site of brain injury by different strategies. In addition, based on our data showing a cooperative effect of complement inhibition and rehabilitation therapy, we will determine the effects of combining site-targeted complement modulation and rehabilitation therapy on long-term cognitive and motor recovery after murine CCI. Successful accomplishment of our aims will provide a strong rationale and establish the feasibility for a Merit proposal for detailed mechanistic studies into the role of C in the chronic neuroinflammatory response after TBI, and the role of the neuroinflammatory response in brain injury, repair and experience-driven (rehab) neural plasticity. These studies will also set the stage for a more detailed preclinical evaluation of an identified candidate drug.